An in vivo genetic reversion highlights the crucial role of Myb-Like, SWIRM, and MPN domains 1 (MYSM1) in human hematopoiesis and lymphocyte differentiation

• Published in: Journal of allergy and clinical immunology Vol. 136; no. 6; pp. 1619 - 1626.e5
• Main Authors: Le Guen, Tangui, Touzot, Fabien, André-Schmutz, Isabelle, Lagresle-Peyrou, Chantal, France, Benoit, Kermasson, Laetitia, Lambert, Nathalie, Picard, Capucine, Nitschke, Patrick, Carpentier, Wassila, Bole-Feysot, Christine, Lim, Annick, Cavazzana, Marina, Callebaut, Isabelle, Soulier, Jean, Jabado, Nada, Fischer, Alain, de Villartay, Jean-Pierre, Revy, Patrick
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.12.2015; Elsevier Limited; Elsevier
• Subjects: Allergy and Immunology; B-Lymphocytes - cytology; Bone marrow; Cell Differentiation; Deoxyribonucleic acid; DNA; DNA methylation; DNA-Binding Proteins - genetics; Epigenetics; Gene expression; genetic reversion; Genomes; Hematopoiesis; Hematopoiesis - genetics; histone deubiquitinase; Humans; immunodeficiency; Immunoglobulins; Immunologic Deficiency Syndromes - genetics; Infant; Life Sciences; Lymphocytes; Lymphopenia - genetics; Male; Mutation; MYSM1; Proteins; Quality; Software; T-Lymphocytes - cytology; Thermal cycling; Transcription Factors - genetics; KO; MYSM1; genetic reversion; APC; Hematopoiesis; JAMM; PE; H2A; HSC; immunodeficiency; histone deubiquitinase; NK; WGHM; WT; JAB1/MPN/Mov34; Knockout; Wild-type; Histone 2A; Hematopoietic stem cell; Natural killer; Myb-Like, SWIRM, and MPN domains 1; Phycoerythrin; Allophycocyanin; Whole-genome homozygosity mapping
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2015.06.008

Myb-Like, SWIRM, and MPN domains 1 (MYSM1) is a metalloprotease that deubiquitinates the K119-monoubiquitinated form of histone 2A (H2A), a chromatin marker associated with gene transcription silencing. Likewise, it has been reported that murine Mysm1 participates in transcription derepression of genes, among which are transcription factors involved in hematopoietic stem cell homeostasis, hematopoiesis, and lymphocyte differentiation. However, whether MYSM1 has a similar function in human subjects remains unclear. Here we describe a patient presenting with a complete lack of B lymphocytes, T-cell lymphopenia, defective hematopoiesis, and developmental abnormalities. We sought to characterize the underlying genetic cause of this syndrome. We performed genome-wide homozygosity mapping, followed by whole-exome sequencing. Genetic analysis revealed that this novel disorder is caused by a homozygous MYSM1 missense mutation affecting the catalytic site within the deubiquitinase JAB1/MPN/Mov34 (JAMM)/MPN domain. Remarkably, during the course of our study, the patient recovered a normal immunohematologic phenotype. Genetic analysis indicated that this improvement originated from a spontaneous genetic reversion of the MYSM1 mutation in a hematopoietic stem cell. We here define a novel human immunodeficiency and provide evidence that MYSM1 is essential for proper immunohematopoietic development in human subjects. In addition, we describe one of the few examples of spontaneous in vivo genetic cure of a human immunodeficiency.